Rutaecarpine prevented ox-LDL-induced VSMCs dysfunction through inhibiting overexpression of connexin 43
Rutaecarpine prevented ox-LDL-induced VSMCs dysfunction through inhibiting overexpression of connexin 43
复制标题
芸香碱通过抑制连接蛋白 43 的过度表达来预防 ox-LDL 诱导的 VSMC 功能障碍
DOI：
10.1016/j.ejphar.2019.03.028
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发表时间：
2019
影响因子：
5
通讯作者：
Luo Dan
中科院分区：
文献类型：
--
作者：
Wang Meiling;Wu Yusi;Yu Yanrong;Fu Yanqi;Yan Hang;Wang Xiaoying;Li Tingting;Peng Weijie;Luo Dan
连接蛋白 43 (Cx43) 的过度表达与血管平滑肌细胞 (VSMC) 功能障碍有关。我们之前的研究报道，草药吴茱萸的活性成分吴茱萸碱可调节人脐静脉内皮细胞中的连接蛋白表达。本研究旨在探讨吴茱萸碱对氧化低密度脂蛋白（ox-LDL）诱导的Cx43表达和VSMCs功能障碍的影响。在培养的大鼠胸主动脉 VSMC 中，ox-LDL 以时间和剂量依赖性方式上调 Cx43 水平，而这种作用可被 NF-κB 抑制剂 BAY11-7082 和 PDTC 消除。此外，暴露于 ox-LDL 4 小时可诱导 VMSC 中 NF-κB p65 的核转位。 Ox-LDL (50mg/l,48h) 诱导 VSMC 功能障碍，表现为细胞过度增殖、迁移和表型转换，通过 Cx43 间隙连接阻断剂 Gap26(100μM) 或吴茱萸碱 (1、3 和 10μM) 处理可减弱这种功能障碍。芸香碱抑制 ox-LDL 诱导的 Cx43 上调，防止 NF-κB p65 的核转位，并增加 VSMC 中的细胞内钙水平。通过使用瞬时受体电位香草酸亚型 1 (TRPV1) 拮抗剂辣椒西平、细胞内钙螯合剂 BAPTA-AM 或 CaM 拮抗剂 W-7 进行预处理，可以消除这些影响。总之，本研究证明吴茱萸碱通过 TRPV1/[Ca2+]i/CaM/NF-κB 信号通路抑制 Cx43 过表达，从而预防 ox-LDL 诱导的 VSMCs 功能障碍。我们的研究提供了芸香碱调节 Cx43 表达和 VSMC 功能的新机制。
Overexpression of connexin 43 (Cx43) was related to dysfunction of vascular smooth muscle cells (VSMCs). Our previous study reported that rutaecarpine, an active ingredient of herbal medicine Evodia, modulated connexins expression in human umbilical vein endothelial cells. This study aims to explore the effects of rutaecarpine on Cx43 expression and VSMCs dysfunction induced by oxidized low-density lipoprotein (ox-LDL). In cultured rat thoracic aortic VSMCs, ox-LDL upregulated the level of Cx43 in a time- and dose-dependent manner, which were abolished by the NF-κB inhibitor BAY11–7082 and PDTC. Furthermore, exposure to ox-LDL for 4 h induced the nuclear translocation of the NF-κB p65 in VMSCs. Ox-LDL (50 mg/l,48 h) induced dysfunction of VSMCs, demonstrated as excessive proliferation, migration, and phenotype switch of cells, which were attenuated by treatment with Cx43 gap junction blocker Gap26(100 μM)) or rutaecarpine (1, 3, and 10 µM). Rutaecarpine inhibited ox-LDL-induced upregulation of Cx43, prevented nuclear translocation of the NF-κB p65, and increased intracellular calcium level in VSMCs. These effects were abolished by pretreatment with transient receptor potential vanilloid subtype 1 (TRPV1) antagonist capsazepine, intracellular calcium chelator BAPTA-AM or CaM antagonist W-7. In conclusion, this study demonstrated that rutaecarpine inhibited Cx43 overexpression through TRPV1/[Ca2+]i/CaM/NF-κB signal pathway, thereby preventing VSMCs dysfunction induced by ox-LDL. Our study provides a novel mechanism by which rutaecarpine modulate Cx43 expression and VSMC function.